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Uveitis is a relatively common disease characterized by inflammation of the eye including the iris, ciliary body and the choroid. Sight threatening complications of uveitis include glaucoma, cataracts and retinal detachment. Neutrophils infiltrate into the eye and cause damage by release of inflammatory products such as superoxide and myeloperoxidase (MPO) (Goto et al., Nippon Ganka Gakkai Zasshi, 98(10):1019-26, 1994; Yamada et al., Journal of free radicals in biology & medicine, 2(2):111-7, 1986; Gritz et al., Current Eye Research, 10(10):927-31, 1991; Graff et al., Journal of pharmacological and toxicological methods, 39(3):169-78, 1998).
Uveitis is broadly categorized into anterior or posterior uveitis depending on the site of inflammation. Typically, anterior uveitis responds to local steroids, although severe posterior inflammation (particularly in patients with bilateral disease or associated systemic autoimmune disease) often requires systemic corticosteroids and/or agents such as methotrexate, cyclosporine A, or cyclophosphamide. Biologics including interferon and inhibitors of TNF, IL-2 and various adhesion molecules have recently introduced as treatment options. However, in some patients inflammation continues despite these therapies and causes permanent visual loss, or treatment is not tolerated because of side effects (Imrie and Dick, Current opinion in ophthalmology, 18(6):481-6, 2007). 5-20% of all blindness results from uveitis and there remains a need for more therapeutic options.
One cytokine involved in inflammatory reactions is granulocyte colony-stimulating factor (G-CSF) which is encoded by the CSF-3 gene. G-CSF is a hemopoietic growth factor that regulates the production of granulocytes (Nicola et al., Nature 314:625, 1985; Metcalf, International Journal of Cancer 25:225, 1980; Nicola et al., Journal of Biological Chemistry 258:9017, 1983). G-CSF mediates its effects through interaction with the G-CSF receptor (G-CSFR, encoded by the CSFR-3 gene), a member of the type I cytokine receptor superfamily (Demetri et al., Blood 78:2791-2808, 1991). Major biological actions of G-CSF in humans and mice include increasing the production and release of neutrophils from the bone marrow (Souza et al., Science 232:61, 1986; Lord et al., Proc. Natl. Acad. Sci. USA 86:9499-9503, 1989), mobilizing hemopoietic progenitor cells from the marrow into the peripheral blood (Bungart et al., British Journal of Haematology 22:1156, 1990; de Haan et al., Blood 86:2986-2992, 1995; Roberts et al., Blood 89:2736-2744, 1997) and modulating the differentiation and effector functions of mature neutrophils (Yong et al., European Journal of Haematology 49:251-259, 1992; Colotta et al., Blood 80:2012-2020, 1992; Rex et al., Transfusion 35:605-611, 1995; Gericke et al., Journal of Leukocyte Biology 57:455-461, 1995; Xu et al., British Journal of Haematology 93:558-568, 1996; Yong, British Journal of Haematology 94:40-47, 1996; Jacob et al., Blood 92:353-361, 1998). G-CSF also acts on mature postmitotic neutrophils after they leave the bone marrow including having effects on phagocytosis (Bialek et al., Infection 26(6):375-8, 1998), apoptosis (Dibbert et al., Proc Natl Acad Sci USA 96(23):13330-5, 1999) and homing (Dagia et al., Nat Med 12(10):1185-90, 2006; Eyles et al., Blood 112(13):5193-201, 2008). G-CSF is used to treat neutropenia, as well as to induce mobilization of hemopoietic stem cells (HSC) for autologous and allogenic stem cell transplantation (Welte et al., Blood 88:1907-1929, 1996).
There are sporadic reports of patients treated with G-CSF experiencing some level of uveitis (Fraunfelder and Harrison, Cornea, 26(3):368-9, 2007; Esmaeli et al., Cornea, 21(6):621-2, 2002; Parkkali et al., Bone Marrow Transplant, 17(3):433-4, 1996; Tsuchiyama et al., Ann Hematol, 79(5):269-71, 2000). However, a number of these reports are in respect of patients with previous episodes of autoimmune disease and/or in combination with other treatment. In addition, some patients with autoimmune disease and suffering from uveitis have increased local and systemic G CSF and G-CSFR levels along with other cytokines and chemokines (Takahama et al., J Dermatol, 21(8):546-52, 1994; Kawakami et al., Arch Dermatol, 140(5):570-4, 2004; Banerjee et al., Investigative Ophthalmology & Visual Science 48(5):2203-2207, 2007). Gene expression analysis of cytokines and their receptors after disease induction in a mouse model of uveitis (Hashida et al., Invest Ophthalmol Vis Sci., 46(11):4224-34 2005) showed that a very large number of different cytokines, cytokine receptors, and chemokines were upregulated following disease induction, including G-CSF and its receptor.
There is a need to develop new treatments for uveitis.